Method of treating metastatic stage prostate cancer

ABSTRACT

The invention provides methods and dosing regimens for treating metastatic stage prostate cancer in a subject using degarelix, as well as related methods of using degarelix in a subject identified as having metastatic stage prostate cancer, and methods of using degarelix to prevent or delay the progression of locally advanced prostate cancer.

This application claims the benefit of priority of U.S. ProvisionalPatent Application No. 61/147,956, filed Jan. 28, 2009, European PatentApplication No. 08250703.9 filed Feb. 29, 2008, and U.S. ProvisionalPatent Application No. 61/027,741, filed Feb. 11, 2008, the entirecontents of all of which are incorporated by reference.

Prostate cancer is a leading cause of morbidity and mortality for men inthe industrialized world, accounting for about 9% of cancer-relateddeaths in men. Prostate cancer is the second leading cause of cancerdeath in American men, behind only lung cancer. The American CancerSociety has estimated that 27,050 men in the United States died ofprostate cancer in 2007. In Europe, prostate cancer is the third mostcommon cause of death from cancer in men in Europe, with 87,400 deathsestimated in 2006 (see Ferlay et al. (2007) Ann. Oncol.; 18:581-92;Lukka et al. (2006) Curr. Oncol.; 13:81-93.).

More than 9 out of 10 prostate cancers are found in the localized andlocally advanced stages. When compared to men of the same age and racewho do not have cancer (relative survival), the 5-year relative survivalrate for the men who are diagnosed as having localized and locallyadvanced stage cancer is nearly 100%. However, the 5-year relativesurvival rate for men with metastatic stage prostate cancer that hasalready spread to distant parts of the body at the time of diagnosis isonly about 32%. (see Cancer Trends Progress Report (http://progressreport.cancer.gov; SEER Program and the National Center for HealthStatistics; http://seer.cancer.gov/). In this last metastatic stage, theaccelerated drop in survival rate is accompanied by symptoms includingpain (e.g. bone pain), weight loss and fatigue. Therefore, treatmentswhich lead to a reduction or staying of bone metastatic tumor cellgrowth would not only provide an increased life expectancy, which may beup to about 3 years or more, but would also provide an improved qualityof life (QoL) as these symptoms are ameliorated.

As the majority of prostate cancers are dependent on testosterone forgrowth, the current medical management of advanced prostate cancerinvolves hormone-based treatments, such as androgen deprivation, whichmay be achieved by bilateral orchiectomy or by administration ofgonadotrophin releasing hormone (GnRH) receptor agonists. Removal of thetestes (castration) was for many years the standard method of preventingthe secretion of male hormones by the gonads as a means for reducinggrowth of prostate cancers. More recently, secretion of male hormoneshas been perturbed by chemical means by interfering with production ofluteinizing hormone (LH), which regulates the synthesis of androgens.Evidence from randomized studies strongly suggests that early endocrinetherapy in non-metastatic, locally advanced disease with or withoutlymph node metastases is associated with a survival benefit (seeGranfors et al. (1998) J. Urol. 159:2030-34; Messing et al. (1999) N.Eng. J. Med. 341:1781-88; and (1997) Br. J. Urol. 79:235-46).

Gonadotrophin releasing hormone (GnRH) is a natural hormone produced bythe hypothalamus that interacts with a receptor in the pituitary tostimulate production of luteinizing hormone (LH). To decrease LHproduction, agonists of the GnRH receptor (GnRH-R), such as leuprolideand goserelin, have been developed. GnRH-R agonists initially act tostimulate LH release and only after prolonged treatment act todesensitize GnRH-R such that LH is no longer produced. The initialstimulation of LH production by the agonist leads to an initial surge inthe production of male sex hormones such that the initial response toagonist therapy is aggravation, rather than amelioration, of thepatient's condition (e.g., tumor growth may increase). This phenomenon,known as the “testosterone surge” or “flare reaction,” can last for aslong as two to four weeks. Additionally, each successive administrationof the agonist can cause an additional small LH surge (known as the“acute-on chronic” phenomenon) that can further worsen the condition.The testosterone surge stimulates prostate cancer and can lead to aworsening of current symptoms or appearance of new symptoms such asspinal cord compression, bone pain and urethral obstruction (Thompson etal. (1990) J. Urol. 140:1479-80; Boccon-Gibod et al. (1986) Eur. Urol.12:400-402). The relative efficacy and safety (including adverse sideeffects) of the GnRH agonist therapy leuprolide (also leuprorelin orLUPRON DEPOT) is known in the art (see e.g., Persad (2002) Int. J. Clin.Pract. 56:389-96; Wilson et al. (2007) Expert Opin. Invest. Drugs16:1851-63; and Berges et al. (2006) Curr. Med. Res. Opin. 22:649-55).One approach that has been taken to avoid the testosterone surge (flarereaction) has been to combine administration of a GnRH-R agonist with anantiandrogen, such as flutamide, known as total androgen ablationtherapy (AAT). Hormonal therapy with a GnRH-R agonist in combinationwith an antiandrogen has been used as a pre-treatment prior to radicalprostatectomy known as adjuvant therapy. The use of antiandrogens,however, is associated with serious hepatic and gastrointestinal sideeffects.

The drawbacks associated with antiandrogens have led to the developmentof antagonists of the gonadotrophin releasing hormone receptor (GnRH-R),to overcome the “testosterone surge” or “flare reaction” associated withGnRH agonists. GnRH antagonists competitively bind to and block the GnRHreceptors and cause a rapid decrease of LH and Follicle StimulatingHormone (FSH) secretion, thereby reducing testosterone production withno initial stimulation/surge. However, GnRH antagonist peptides arefrequently associated with the occurrence of histamine-releasingactivity. This histamine-releasing activity represents a seriousobstacle to the clinical use of such antagonists because histaminerelease results in adverse side effects such as edema and itching.

The search for improved GnRH antagonists has resulted in the making ofAntide, Cetrorelix and Antarelix (U.S. Pat. No. 5,516,887). GnRHantagonists having such significantly modified or unnatural amino acidsin the 5- and 6-positions exhibit good biological potency, and thosebuilt upon Aph are generally considered to be particularly potent. Onethat is especially useful is Azaline B. U.S. Pat. No. 5,506,207 alsodiscloses biopotent GnRH antagonists with acylated, amino-substitutedphenylalanine side chains of residues in the 5- and 6-positions; onesuch decapeptide is Acyline.

Despite the attractive properties of this group of GnRH antagonists,adverse effects have been observed. The relative efficacy and safety(including adverse side effects) of the GnRH antagonist abarelix(PLENAXIS) has been reported (see, e.g., Mongiat-Artus et al. (2004)Expert Opin. Pharmacother. 5:2171-9; and Debruyne et al. (2006) FutureOncol. 2:677-96). As such, the search has continued for still furtherimproved GnRH antagonists, particularly those which combine longduration of biological action, and improved safety profile.

These desirable features have been addressed in several issued patentsand patent applications, relating to a GnRH antagonist, degarelix, fortreatment of prostate cancer (see, e.g., EP 1003774, U.S. Pat. No.5,925,730, U.S. Pat. No. 6,214,798, EP 02749000.2 and U.S. Ser. No.12/155,897 and EP 08250703.9, the contents of which are herebyincorporated in their entirety). In addition, U.S. Ser. No. 61/027,742discloses the results of a long term evaluation in a multicentrerandomized clinical study which demonstrate that degarelix iswell-tolerated without evidence of systemic allergic reactions.Degarelix treatment also resulted in fast, profound and sustainedsuppression of testosterone (T) without T surge, as well as goodefficacy and safety findings.

However, although continued investigations have allowed progress in thegeneral prevention and treatment of prostate and other cancers, therehas been little or no focus on addressing patients suffering at the latemetastatic stage of cancer.

SUMMARY OF THE INVENTION

The invention is based, in part, upon the surprising finding thatadministration of the GnRH antagonist degarelix to patients withmetastatic stage prostate cancer, and/or to patients having PSA levelsof 50 ng/mL or greater, provides a remarkable, and long term, reductionof serum alkaline phosphatase (S-ALP) that is indicative of bettercontrol of (e.g. skeletal) metastases (see Example 1, FIGS. 1-4, Table2). The results further evidence that administration of degarelix delaysor prevents progression from localized or locally advanced stageprostate cancer to metastatic stage. Further, the results evidence thatadministration of degarelix to these patients is associated with a delayin progression to hormone refractory stage. Notably, this remarkablelong term reduction of S-ALP is not shown following administration ofthe GnRH agonist leuprolide.

In a first aspect, the invention provides a method of treatingmetastatic stage prostate cancer in a subject. The method includes theinitial step of identifying a suitable subject with metastatic stageprostate cancer, and then administering an initial dose of degarelix of160 to 320 mg to the subject. The subject is then administered amaintenance dose of degarelix of 60 to 160 mg once every 20 to 36 daysthereafter. The method thereby treats the metastatic stage prostatecancer in the subject. In a particular aspect, the invention provides amethod of treating metastatic stage prostate cancer in a subject, whichincludes the initial step of identifying a suitable subject withmetastatic stage prostate cancer, and then administering an initial doseof degarelix of about 240 mg to the subject. The subject is thenadministered a maintenance dose of degarelix of 60 to 160 mg once every20 to 36 days thereafter. The method thereby treats the metastatic stageprostate cancer in the subject.

In certain embodiments of the methods of the invention, the subject tobe treated is identified by testing the serum alkaline phosphatase(S-ALP) level of a potential subject and then selecting the subject fortreatment if the subject's baseline S-ALP level is 150 IU/L or greater,e.g. 160 IU/L or greater. In further embodiments, the subject to betreated is identified by testing the serum alkaline phosphatase (S-ALP)level of a potential subject and then selecting the subject fortreatment if the subject's baseline S-ALP level is 200 IU/L or greater.In still further embodiments, the subject to be treated is identified bytesting the serum alkaline phosphatase (S-ALP) level of a potentialsubject and then selecting the subject for treatment if the subject'sbaseline S-ALP level is 300 IU/L or greater.

In further embodiments of the methods of the invention, the subject tobe treated is identified by testing the hemoglobin (Hb) level of apotential subject and then selecting the subject for treatment if thesubject's Hb level is 130 g/L or less. In still further embodiments, thesubject to be treated is identified by testing the prostate-specificantigen (PSA) level of a potential subject and then selecting thesubject for treatment if the subject's PSA level is greater than orequal to 50 ng/mL. In particular embodiments, the treated subject'sS-ALP is reduced by at least 60 IU/L from the baseline level between day112 and day 364 of treatment.

In further embodiments of the methods of the invention, the treatedsubject's serum alkaline phosphatase (S-ALP) is reduced by at least 50IU/L from the baseline level between day 60 and day 364 of treatment. Inother embodiments, the treated subject's S-ALP is reduced by at least 50IU/L from the baseline level between day 364 and day 450 of treatment.In further embodiments, the treated subject's S-ALP is reduced by atleast 90 IU/L from the baseline level between day 112 and day 364 oftreatment. In still further embodiments, the treated subject's S-ALP isreduced by at least 160 IU/L from the baseline level between day 112 andday 364 of treatment.

In further embodiments of the methods of the invention, the treatedsubject has at least a 95% likelihood of having a therapeutically lowserum testosterone level of less than or equal to 0.5 ng/mL by day 28 oftreatment. In particular embodiments, the treated subject has at least a95% likelihood of maintaining a therapeutically low serum testosteronelevel of less than or equal to 0.5 ng/mL from day 28 to day 365 oftreatment.

In still further embodiments of the methods of the invention, thetreated subject has at least a 60% decrease in the level ofprostate-specific antigen (PSA) by day 14 of treatment. In certainembodiments, the treated subject has at least a 75% decrease in thelevel of PSA by day 28 of treatment. In further embodiments, the treatedsubject has at least an 80% likelihood of maintaining aprostate-specific antigen (PSA) level of less than 5 ng/mL duringtreatment.

In another aspect, the invention provides a method of treating prostatecancer by first testing the prostate-specific antigen (PSA) of apotential subject, and then selecting the potential subject fortreatment if the subject's PSA level is greater than or equal to 50ng/mL. The method further includes the steps of administering an initialdose of degarelix of 160 to 320 mg to the subject thus identified, andthen administering a maintenance dose of degarelix of 60 to 160 mg tothe subject once every 20 to 36 days thereafter, so as to treat theprostate cancer in the subject.

In certain embodiments of the methods of the invention, the subject tobe treated is further identified by testing the serum alkalinephosphatase (S-ALP) level of a potential subject and then selecting thesubject for treatment if the subject's baseline S-ALP level is 150 IU/Lor greater, e.g. 160 IU/L or greater. In certain embodiments, thetreated subject's S-ALP is reduced by at least 60 IU/L from the baselinelevel between day 112 and day 364 of treatment. In further embodiments,the subject to be treated is further identified by testing thehemoglobin (Hb) level of the potential subject and then selecting thesubject for treatment if the subject's Hb level is 130 g/L or less.

In another aspect, the invention provides methods of using degarelix forthe treatment of metastatic stage prostate cancer in a subject. Themethods of use of degarelix include an initial step of identifying asuitable subject with metastatic stage prostate cancer. The suitablesubject thus identified is then administered an initial dose ofdegarelix of 160 to 320 mg, followed by maintenance doses of 60 to 160mg of degarelix once every 20 to 36 days thereafter, thereby usingdegarelix for the treatment of metastatic stage prostate cancer.

In certain embodiments of the methods of use of degarelix, the subjectwith metastatic stage prostate cancer is identified by testing the serumalkaline phosphatase (S-ALP) level of a potential subject and thenselecting the subject for treatment if the subject's baseline S-ALPlevel is 150 IU/L or greater, e.g. 160 IU/L or greater. In furtherembodiments, the subject with metastatic stage prostate cancer isidentified by testing the serum alkaline phosphatase (S-ALP) level of apotential subject and then selecting the subject for treatment if thesubject's baseline S-ALP level is 200 IU/L or greater. In still furtherembodiments, the subject with metastatic stage prostate cancer isidentified by testing the serum alkaline phosphatase (S-ALP) level of apotential subject and then selecting the subject for treatment if thesubject's baseline S-ALP level is 300 IU/L or greater. In certainembodiments, the subject with metastatic stage prostate cancer isidentified by testing the hemoglobin (Hb) level of a potential subjectand then selecting the subject for treatment if the subject's Hb levelis 130 g/L or less. In other embodiments, the subject with metastaticstage prostate cancer is identified by testing the prostate-specificantigen (PSA) level of a potential subject and then selecting thesubject for treatment if the subject's PSA level is greater than orequal to 50 ng/mL.

In another aspect, the invention provides methods of using degarelix toprevent or delay the progression of localized or locally advancedprostate cancer to metastatic stage prostate cancer in a subject. Themethods of use of degarelix to prevent or delay the progression oflocalized or locally advanced prostate cancer include the initial stepof identifying a suitable subject with localized or locally advancedprostate cancer. The suitable subject thus identified is thenadministered an initial dose of degarelix of 160 to 320 mg, followed bymaintenance doses of 60 to 160 mg of degarelix once every 20 to 36 daysthereafter. This method of use of degarelix thereby prevents or delaysthe progression of localized or locally advanced prostate cancer tometastatic stage prostate cancer in the subject.

In certain embodiments of the methods of use of degarelix to prevent ordelay metastatic stage prostate cancer, the subject with localized orlocally advanced prostate cancer is identified by testing theprostate-specific antigen (PSA) level of a potential subject and thenselecting the subject for preventive or delaying treatment if thesubject's PSA is 10-50 ng/mL. In further embodiments, the subject withlocalized or locally advanced prostate cancer is identified by testingthe prostate-specific antigen (PSA) level of a potential subject andthen selecting the subject for preventive or delaying treatment if thesubject's PSA is 20-50 ng/mL. In further embodiments, the subject withlocalized or locally advanced prostate cancer is identified by testingthe serum alkaline phosphatase (S-ALP) level of between 44 and 147 IU/L.In still further embodiments, the subject with localized or locallyadvanced prostate cancer is identified by testing the serum alkalinephosphatase (S-ALP) level of a potential subject and then selecting thesubject for preventive or delaying treatment if the subject's baselineS-ALP level is less than about 160 IU/L. In certain embodiments, thesubject with localized or locally advanced prostate cancer is identifiedby testing the serum alkaline phosphatase (S-ALP) level of a potentialsubject and then selecting the subject for preventive or delayingtreatment if the subject's baseline S-ALP level is, for example 44 to147 IU/L and/or between 50 and 160 IU/L.

In a further aspect, the invention provides a composition (e.g. apharmaceutical composition, a medicament) comprising degarelix for thetreatment of metastatic stage prostate cancer in a subject.

As used herein, the term metastasis refers to a secondary metastaticgrowth of a malignant tumor that forms when cancer has spread from anoriginal site to more remote or distant parts of the body, for examplethe lymph nodes, bone, and/or other organs such as the brain or liver.Thus, the term “metastatic” or “metastatic stage prostate cancer” refersto a cancer that has spread to distant organs from the original tumoursite, e.g., the prostate gland.

Herein, “treatment of metastatic stage prostate cancer” and associatedmethods of “treating metastatic stage prostate cancer” includetreatments and associated methods to reduce the amount of canceroustissue, e.g. by reducing the number and/or size of metastatic lesions(tumors), such as metastatic lesions in the bone, brain, liver and/orlymph nodes. As used herein, the “treatment of metastatic stage prostatecancer” and associated methods of “treating metastatic stage prostatecancer” refer particularly to treatments, and associated methods, toreduce skeletal metastases (metastatic lesions identified in theskeleton, e.g., by bone scan or other imaging technique).

Herein, “treatment of metastatic stage prostate cancer” and associatedmethods of “treating metastatic stage prostate cancer” further Includetreatments and associated methods to reduce and/or ameliorate one ormore symptoms associated with metastatic stage prostate cancer, e.g.treatment to ameliorate and/or reduce the symptoms of urinary disorders(e.g. obstruction, weak or interrupted urination, frequent urination,inability to urinate, pain while urinating, blood in the urine),treatment to reduce and/or ameliorate bone pain (e.g. in the lower back,hips or thighs), and/or treatment to reduce and/or ameliorate weightloss, fatigue.

In another aspect of the invention, there is provided a compositioncomprising degarelix for the treatment of metastatic stage prostatecancer in a subject to reduce the number and/or size of metastaticlesions and/or to reduce and/or ameliorate one or more symptomsassociated with metastatic stage prostate cancer.

The terms “prevention of metastatic stage prostate cancer” andassociated methods of “preventing metastatic stage prostate cancer”further include treatments, and associated methods that prevent theonset of metastatic activity or that maintains the level of metastaticactivity (e.g. at the level known at start of medication, i.e.baseline), or that reduce and/or delay the return of metastatic activity(e.g. as measured by S-ALP), in a subject being treated for prostatecancer who is at the locally advanced stage. The expression “the levelof metastatic activity” in this context refers to the size and/or numberof metastatic tumors in the subject, and not the rate of metastasis inthe subject per se.

Accordingly, the invention includes treatments and associated methods todelay or prevent progression of the disease and/or to bring on orenhance regression or remission of the disease. For example, the term“prevention of metastatic stage prostate cancer” and associated “methodsof preventing metastatic stage prostate cancer” include treatments andassociated methods to prolong the life and/or increase the quality oflife (QoL) of the patient.

Herein the terms “treatment of metastatic [stage] prostate cancer” andassociated “methods of treating metastatic [stage] prostate cancer”, or,“treatment of prostate cancer” and associated “methods of treatingprostate cancer” may also include treatments and associated methods thatdelay or prevent onset of the hormone-refractory disease stage.

Thus, according to the present invention in yet another aspect, there isprovided a composition comprising degarelix for the treatment ofprostate cancer in a subject and associated methods of treatment thatreduce the likelihood of, and/or delay, the return of metastatic tumoractivity, and/or that delay or prevent progression of the disease,and/or bring on or increase regression or remission of the disease,and/or prolong the life and/or increase the quality of life (QoL) of thepatient, and/or delay or prevent onset of the hormone-refractory diseasestage.

The term “treatment of prostate cancer” and associated “methods oftreating prostate cancer” also include treatment and associated methodsto cure the prostate cancer.

Applicants now disclose that the administration of the GnRH antagonistdegarelix to patients with metastatic stage prostate cancer and/orpatients having PSA level of about 50 ng/mL or greater, provides aremarkable, and long term, reduction of serum alkaline phosphatase(S-ALP) (See FIGS. 1 and 4, Table 2). Not only is the reduction in theS-ALP value significant, but more importantly, the steady and maintainedlow levels of S-ALP levels over a long term period (See FIG. 3), isindicative of better control of (e.g. bone) metastases. This remarkablelong term reduction of S-ALP is not shown following administration ofthe GnRH agonist leuprolide.

The remarkable long term reduction of S-ALP following administration ofthe GnRH antagonist degarelix to patients with metastatic stage prostatecancer and/or patients having PSA level of about 50 ng/mL or greateralso provides evidence that administration of degarelix to thesepatients provides a delay in progression of the cancer to the hormonerefractory stage.

The subject may have a baseline serum alkaline phosphatase (S-ALP) level(that is, a S-ALP level prior to treatment i.e. prior to administrationof the initial dose of testosterone) of about 150 IU/L or greater, e.g.,a baseline serum alkaline phosphatase (S-ALP) level of about 160 IU/L orgreater, e.g., a baseline serum alkaline phosphatase (S-ALP) level ofabout 200 IU/L or greater, or even a baseline serum alkaline phosphatase(S-ALP) level of about 300 IU/L or greater (See Table 2).

In further embodiments, the degarelix composition provides a reductionbelow the baseline (or alternatively articulated, a negative change frombaseline) of serum alkaline phosphatase (S-ALP) level of at least about50 IU/L below the baseline (S-ALP) for a period between about 60 and 364days after administration of the initial dose of degarelix, and/or, atleast about 90 IU/L below the baseline level for a period between 112and 364 days after administration of the initial dose of degarelix. (SeeTable 2, FIGS. 1-3). In certain embodiments, reduction in serum alkalinephosphatase (S-ALP) level of at least about 50 IU/L below the baselinelevel extends for a period beyond 364 days (depending on continuation oftherapy/maintenance doses, see below).

In still further embodiments, the subject to whom the treatment isadministered has a hemoglobin (Hb) level of about 130 g/L or less.Baseline S-ALP levels were particularly elevated in the subgroup ofpatients with metastatic disease and Hb<130 g/L; for example a baselineserum alkaline phosphatase (S-ALP) level of 300 IU/L or greater wasfound in a population of patients having a Hb<130 g/L (See Table 2). Inparticular embodiments, the subject with the aforementioned depressed Hblevel also shows a reduction (alternatively, a negative change frombaseline) of serum alkaline phosphatase (S-ALP) level of at least 160IU/L below the baseline level for a period between 112 and 364 daysafter administration of the initial dose of degarelix (See FIG. 2). Bonemetastases affect bone marrow and a patient with bone metastasis maybecome anemic; thus lower than normal Hb in patients with bonemetastasis is indicative of greater degree of metastasis (more seriousdisease). As described in further detail herein, the invention providesa surprisingly long term and effective suppression of S-ALP by degarelixin this sub-population of patients with lower than normal Hb levels.

According to the present invention in a further aspect, there isprovided a composition comprising degarelix for the treatment ofprostate cancer in a subject having a prostate specific androgen (PSA)level of greater than or equal to 50 ng/mL (See FIG. 4). In particularembodiments, the prostate cancer to be treated is metastatic prostatecancer.

In aspects of the invention, the composition may be for administrationof degarelix at an initial dose of 160 to 320 mg; and at a maintenancedose of 60 to 160 mg, once every 20 to 36 days thereafter, for examplefor administration at an initial dose of degarelix of about 240 mg; andat a maintenance dose of about 80 mg degarelix once every approximately28 days of treatment.

In certain embodiments, the composition of degarelix is for treatmentwherein the subject has at least a 95% likelihood of maintaining atherapeutically low serum testosterone level of less than or equal to0.5 ng/mL by day 28 of treatment, for example wherein the subject has atleast a 95% likelihood of maintaining a therapeutically low serumtestosterone level of less than or equal to 0.5 ng/mL from day 28 to day364 of treatment. (See, e.g., FIGS. 7-8).

In still further embodiments, the composition of degarelix is fortreatment of metastatic prostate cancer and provides a 60% decrease inPSA by day 14 of treatment. In still further embodiments, thecomposition (or medicament) of degarelix provides at least a 60%decrease, e.g., at least a 75% decrease, in prostate specific antigen(PSA) by day 28 of treatment. (See, e.g., FIG. 9).

In further embodiments, the composition of degarelix is for treatmentwith at least an 80%; for e.g., a 95% likelihood, of maintaining aprostate specific antigen (PSA) level of less than 5 ng/mL duringtreatment.

According to another aspect of the invention, there is provided a methodof treating metastatic prostate cancer in a subject comprisingadministering an initial dose of 160-320 mg of degarelix to the subject;and administering a maintenance dose of 60-160 mg of degarelix to thesubject once every 20-36 days thereafter; for example, administering aninitial dose of about 240 mg of degarelix to the subject; andadministering a maintenance dose of about 80 mg of degarelix to thesubject once every approximately 28 days thereafter.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a graphical representation comparing the mean change inbaseline S-ALP levels versus time, for the local (localized), locallyadvanced and metastatic populations, using degarelix (240/80 mg) andleuprolide (7.5 mg) treatments.

FIG. 2 is a graphical representation showing the mean change in baselineS-ALP levels, versus time, for the Metastatic (+Hb<130 g/L)subpopulation using degarelix (240/80 mg), degarelix (240/160 mg) andleuprolide (7.5 mg) treatments.

FIG. 3 is a graphical representation showing the mean change in baselineS-ALP values, versus time, using degarelix (240/80 mg) treatment ascompared to leuprolide (7.5 mg) treatment that was “switched” todegarelix after day 364, which demonstrates the difference in time forthe reduced baseline S-ALP values to return to baseline level.

FIG. 4 is a graphical representation comparing the mean change inbaseline S-ALP values, versus time, in subjects having PSA levels of <10ng/mL, 10-20 ng/mL, 20-50 ng/mL, and >50 ng/mL, using degarelix (240/80mg) and leuprolide (7.5 mg) treatments.

FIG. 5 is a graphical representation showing the incidence of PSAfailure in subjects with baseline localized, locally advanced, andmetastatic prostate cancer stages, using degarelix (240/80 mg) andleuprolide (7.5 mg) treatments.

FIG. 6 is a graphical representation showing the incidence of PSAfailure in subjects with baseline PSA levels of <10 ng/mL, 10-20 ng/mL,20-50 ng/mL, and ≧50 ng/mL, using degarelix (240/80 mg) and leuprolide(7.5 mg) treatments.

FIG. 7 is a graphical representation showing the decrease in mediantestosterone levels from day 0 to day 364, using degarelix (240/80 mg)and leuprolide (7.5 mg) treatments.

FIG. 8 is a graphical representation showing the median percentagechange in testosterone level from day 0 to day 28, using degarelix(240/80 mg) and leuprolide (7.5 mg) treatments.

FIG. 9 is a graphical representation showing the median percentagechange in PSA level from day 0 to day 56, using degarelix (240/80 mg)and leuprolide (7.5 mg) treatments.

FIG. 10 is a graphical representation showing the median LH level fromday 0 to day 364, using degarelix (240/160 mg), degarelix (240/80 mg)and leuprolide (7.5 mg) treatments.

FIG. 11 is a graphical representation showing the median FSH level fromday 0 to day 364, using degarelix (240/160 mg), degarelix (240/80 mg)and leuprolide (7.5 mg) treatments.

DETAILED DESCRIPTION OF THE INVENTION

Terms and Definitions

Particular aspects of the invention are described in greater detailbelow. The terminologies and definitions as used in the presentapplication as clarified herein are intended to represent the meaning ofthe applicants in their disclosure of the invention. The patent andscientific literature referred to herein are hereby incorporated byreference in their entireties.

The singular forms “a,” “an,” and “the” include plural reference unlessthe context clearly dictates otherwise.

The terms “approximately” and “about” mean to be nearly the same as areferenced number or value. As used herein, the terms “approximately”and “about” should be generally understood to encompass ±10% of aspecified amount, frequency or value. The term “Cl” refers to astatistical confidence interval. With regard to specific values of,e.g., serum alkaline phosphatase (S-ALP), prostate specific antigen(PSA), hemoglobin (Hb), testosterone, luteinizing hormone (LH), andfollicle stimulating hormone (FSH), it should be understood thatspecific values described herein for subject populations (e.g., thesubjects of clinical study CS21, described below) represent average(i.e., mean values), unless otherwise noted as, e.g., median values.Accordingly, aspects of the invention requiring a particular value ofS-ALP, PSA, and/or Hb level in a subject are substantially supportedherein by population data in which the relevant value is assessed to bea meaningful delimitation of the subject population.

In general, the invention provides use of a composition comprisingdegarelix GnRH antagonist for treating metastatic prostate cancer in asubject, and related methods of treatment. The disclosure of theinvention has been exemplified by data obtained from clinical studies,in particular, the CS21 study on Degarelix (EP application No.08250703.9, and U.S. provisional application No. 61/027,741). A reviewof the basic methods for conducting and analyzing the type of controlledclinical studies described herein, including analyses of safety,efficacy and selective advantages to certain patient subpopulations, isavailable (see Spilker (1991) Guide to Clinical Trials Raven Press, NewYork; and Spilker (1996) Quality of Life and Pharmacoeconomics inClinical Trials Lippincott—Raven Publishers New York).

The term “prostate cancer” refers to any cancer of the prostate gland inwhich cells of the prostate mutate and begin to multiply out of control.The extent to which prostate cancer has progressed in a patient isassessed taking into account clinical and histopathological information.The stage of cancer is classified based on tumour size (T), whetherthere is lymph node involvement (N), the presence of metastasis (M), andthe tumour grading (G). A tumour classed as T1 is confined to theprostate gland and too small to be felt by digital rectal examination.T1 further includes T1a (fewer than 5% cancerous cells in tissue sample)and T1b (more than 5%) subdivisions. T1c indicates the patient has anelevated Prostrate Specific Antigen (PSA; see definition later). If thetumour is large enough to be felt during a digital rectal examination,it is classified as T2. T2a means only one side of the prostate gland(left or right) is involved; T2b means both sides have a tumour(s). T2is commonly termed “localized cancer”. If the cancer is T3, it hasspread to the connected tissue near the prostate (T3a) or the seminalvesicles (T3b). T4 indicates cancer spread to tissue next to theprostate, for example the bladder sphincter, rectum or pelvis wall. Theprostate cancer may also spread into the regional lymph nodes of thepelvis and this is assessed as N1 stage of prostate cancer. These stagesof T3, T4 and N1 are collectively termed “locally advanced” or regionalcancer. If the cancer has spread to distant sites, such as the bone, itis said to be “metastasized” or at the M1 stage. Prostate cancer thathas spread to distant lymph nodes is categorized as M1a while that whichhas spread to bone is M1b and that which has spread to organs such asliver or brain is assessed as M1c. Left untreated, prostate canceralmost universally metastasizes to bone.

Terms as used in this application, such as “bone metastasis”, “skeletalmetastases”, “bone lesions”, “metastatic lesions” refer to themetastatic stage and may be used interchangeably. Pain (e.g. bone pain),weight loss and fatigue often accompany the M1 stage. Survival rate alsodrops significantly for subjects with metastatic prostate cancer.Treatments which lead to a reduction of bone metastasis imply not onlyan improved quality of life (QoL), such as decreased pain, bone loss,but more significantly, an increased life expectancy, up to about 3years or more. At a certain point, however, metastatic patients may failto respond to hormone-based treatments; this is known as the“hormone-refractory” disease stage. According to this terminology, andas adopted in this application, the term “treatment of metastaticprostate cancer” includes treatment of a subject who is classified asM1a, M1b or M1c, and/or N1.

In general, androgen deprivation induces a remission in 80 to 90 percentof men with advanced prostate cancer, and results in a medianprogression free survival of 12 to 33 months. At that time, an androgenindependent phenotype usually emerges. Hormone refractory prostatecancer (which may also be referred to as hormone-resistant prostatecancer or hormone independent prostate cancer) is broadly defined hereinas prostate cancer wherein the patient's blood PSA is rising despitehaving a castrate level of testosterone (T less than 20 ng/dL) caused byhormone blockade therapy. [Murphy D. (1993) Cancer 72: 3888-3895;Hellerstedt B A and Pienta K J (2002) CA Cancer J. Clin. 52: 154-179.]

Alkaline phosphatase (ALP) is a hydrolase enzyme responsible forremoving phosphate groups from many types of molecules, includingnucleotides, proteins, and alkaloids. In humans, ALP is present in alltissues throughout the entire body, but is particularly concentrated inliver, bile duct, kidney, bone and the placenta. Its concentration levelmay be used as a diagnostic tool; abnormally elevated levels(hyperphosphatasemia) may indicate several disorders. These includeliver disease, bone disease, skeletal involvement of other primarydiseases such as malignant tumours, osteomalacia, renal disease(secondary hypothyroidism), and primary hypothyroidism. On the otherhand, abnormally lowered levels of ALP (hypophosphatasemia) may indicateother disorders, such as severe anemia in men, or achondroplasia,cretinism, or severe enteritis in children. In general, levels of ALPpresent in a subject's serum (S-ALP levels) are used in conjunction withthe treatment methods and compositions described herein.

S-ALP testing is well known in the art (Chernecky C C, Berger B J(2008), Laboratory Tests and Diagnostic Procedures, 5th ed., WB Saunders& Company, Philadelphia). It is generally used as a test of liverfunction, but is also known as an indicator for metastatic lesions inthe bone for different malignancies (breast, prostate and colon). Inmetastatic prostate cancer, baseline S-ALP levels (or alternatively,“ALP levels”) are consistently higher than in localized or locallyadvanced disease reflecting bone lesions. As disclosed in the presentinvention, the subject may have a baseline serum alkaline phosphatase(S-ALP) level (that is, a S-ALP level prior to treatment i.e. prior toadministration of the initial dose of testosterone) of 160 IU/L orgreater, for example a baseline serum alkaline phosphatase (S-ALP) levelof 200 IU/L or greater. A decrease in baseline S-ALP levels in a treatedsubject suffering from metastatic prostate cancer therefore demonstratesa positive response to the treatment in certain circumstances.

One of the most important techniques for diagnosis of prostate cancer isblood testing; specifically, in the measurement of prostate-specificantigen (PSA) levels in the blood. The term “prostate-specific antigen”or “PSA” refers to a protein produced by cells of the prostate glandthat is present in small quantities in the serum of normal men, but isoften elevated in the presence of prostate cancer and in other prostatedisorders. A blood test to measure PSA is the most effective testcurrently available for the early detection of prostate cancer. Levelsof PSA, which are higher than normal, are associated with both localizedand metastatic prostate cancer. According to the present invention, thesubjects with localized or metastatic stage prostate cancer have aprostate specific androgen (PSA) level of greater than or equal to 50ng/mL.

Degarelix and Related Pharmaceutical Formulations

Degarelix is a potent GnRH antagonist that is an analog of the GnRHdecapeptide (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH₂) incorporatingp-ureido-phenylalanines at positions 5 and 6 (Jiang et al. (2001) J.Med. Chem. 44:453-67). It is indicated for treatment of patients withprostate cancer in whom androgen deprivation is warranted (includingpatients with rising PSA levels after having already undergoneprostatectomy or radiotherapy).

Degarelix is a selective GnRH receptor antagonist (blocker) thatcompetitively and reversibly binds to the pituitary GnRH receptors,thereby rapidly reducing the release of gonadotrophins and consequentlytestosterone (T). Prostate cancer is sensitive to testosteronedeprivation, a mainstay principle in the treatment of hormone-sensitiveprostate cancer. Unlike GnRH agonists, GnRH receptor blockers do notinduce a luteinizing hormone (LH) surge with subsequent testosteronesurge/tumor stimulation and potential symptomatic flare after theinitiation of treatment.

The active ingredient degarelix is a synthetic linear decapeptide amidecontaining seven unnatural amino acids, five of which are D-amino acids.The drug substance is an acetate salt, but the active moiety of thesubstance is degarelix as the free base. The acetate salt of degarelixis a white to off-white amorphous powder of low density as obtainedafter lyophilisation. The chemical name is D-Alaninamide,N-acetyl-3-(2-naphthalenyl)-D-alanyl-4-chloro-D-phenylalanyl-3-(3-pyridinyl)-D-alanyl-L-seryl-4-[[[(4S)-hexahydro-2,6-dioxo-4-pyrimidinyl]carbonyl]amino]-Lphenylalanyl-4-[(aminocarbonyl)amino]-D-phenylalanyl-Lleucyl-N-6-(1-methylethyl)-L-lysyl-L-prolyl. It has an empirical formulaof C₈₂H₁₀₃N₁₈O₁₆Cl and a molecular weight of 1,632.3 Da. The chemicalstructure of degarelix has been previously shown (EP 1003774, U.S. Pat.No. 5,925,730, U.S. Pat. No. 6,214,798) and may be represented by theformula:

-   Ac-D-NaI-D-Cpa-D-PaI-Ser-Aph(Hor)-D-Aph(Cbm)-Leu-Lys(iPr)-Pro-D-Ala-NH₂.    Administration and Dosing

Degarelix may be formulated for administration subcutaneously (asopposed to intravenously), generally in the abdominal region, asdescribed in further detail below. As with other drugs administered bysubcutaneous injection, the injection site may vary periodically toadapt the treatment to injection site discomfort. In general, injectionsshould be given in areas where the patient will not be exposed topressure, e.g. not close to waistband or belt and not close to the ribs.

Administration of degarelix by subcutaneous or intramuscular injectionworks well, but daily injections are generally not acceptable and so adepot formulation of degarelix may be utilized as describe in furtherdetail in WO 03/006049 and U.S. Pub. Nos. 20050245455 and 20040038903.Briefly, subcutaneous administration of degarelix may be conducted usinga depot technology in which the peptide is released from a biodegradablepolymer matrix over a period of (typically) one to three months.Degarelix (and related GnRH antagonist peptides) have a high affinityfor the GnRH receptor and are much more soluble in water than other GnRHanalogues. Degarelix and these related GnRH antagonists are capable offorming a gel after subcutaneous injection, and this gel can act as adepot from which the peptide is released over a period of weeks or evenmonths.

A key variable for formation of an effective degarelix depot is theconcentration of the solution in combination with the amount ofsubstance administered per se. The concentration must be within afunctional range. If the formulation is too dilute then no depot isformed and the long duration of action is lost, regardless of the amountof drug substance given. If the formulation is too concentrated then gelformation will occur before the drug can be administered. Effectivedepot-forming formulations of degarelix generally have a concentrationof not less than 5 mg/mL degarelix, e.g. 5 to 40 mg/mL of degarelix.

Thus, degarelix may be provided as a powder for reconstitution (with asolvent) as solution for injection (e.g., subcutaneous injection, e.g.,to form a depot as described above). The powder may be provided as alyophilisate containing degarelix (e.g. as acetate) and mannitol. Asuitable solvent is water (e.g., water for injection, or WFI). Forexample, degarelix may be provided in a vial containing 120 mg degarelix(acetate) for reconstitution with 3 mL WFI such that each mL of solutioncontains about 40 mg degarelix. In another example, degarelix may beprovided in a vial containing 80 mg degarelix (acetate). Afterreconstitution with about 4 mL (e.g., 4.2 mL) WFI, each mL solutioncontains about 20 mg degarelix.

According to the invention, there is provided a method of treatingmetastatic prostate cancer in a subject comprising administering aninitial dose of 160-320 mg of degarelix to the subject; andadministering a maintenance dose of 60-160 mg of degarelix to thesubject once every 20-36 days thereafter; for example, administering aninitial dose of about 240 mg of degarelix to the subject; andadministering a maintenance dose of about 80 mg of degarelix to thesubject once every approximately 28 days thereafter.

The composition may be for administration of degarelix at an initialdose of 160 to 320 mg; and at a maintenance dose of 60 to 160 mg, onceevery 20 to 36 days thereafter.

A preferred dosing regimen for treating adult males with prostate canceris a single 240 mg starting dose of degarelix administered as twosubcutaneous injections of 120 mg; and followed by monthly maintenancedoses of 80 mg of degarelix administered as a single subcutaneousinjection beginning approximately 28 days or one month after the initialstarting dose.

For example, the dosing regimen for degarelix may be administered as aninitial, starting dose of 240 mg administered as 2 injections of 3 mL ofabout 40 mg/mL degarelix formulation, followed by monthly maintenancedoses of 80 mg administered as a single injection of 4 mL of about 20mg/mL degarelix formulation. Alternatively, monthly maintenance doses of160 mg may be utilized, e.g., by administering 4 mL of about 40 mg/mLdegarelix every month.

The reconstituted solution should be a clear liquid, free of undissolvedmatter. A single dose of 240 mg degarelix, followed by a monthlymaintenance dose of 80 mg, rapidly causes a decrease in theconcentrations of the luteinizing hormone (LH), follicle stimulatinghormone (FSH), and subsequently testosterone. The plasma concentrationof dihydrotestosterone (DHT) decreases in a manner similar to that oftestosterone.

Degarelix is effective in achieving and maintaining testosteronesuppression well below medical castration level of 0.5 ng/mL. Asdescribed below in further detail, maintenance monthly dosing of 80 mgresulted in sustained testosterone suppression in 97% of patients for atleast one year. In particular, the median testosterone level after oneyear of such treatment was 0.087 ng/mL.

The relevant pharmacokinetic parameters for degarelix evaluated inprostate cancer patients are summarized in Table 1, below.

TABLE 1 Degarelix pharmacokinetic parameters after subcutaneousadministration of 240 mg at a concentration of 40 mg/mL Pharmacokineticdegarelix parameter 240 mg Cmax (ng/mL) 53.4 Tmax (days) 1.4 T½ (days)43 AUC (day · ng/mL) 1240

Median degarelix trough concentrations in the maintenance phase with 80mg at a concentration of 20 mg/mL was 10.9 ng/mL.

Following subcutaneous administration of 240 mg degarelix (6 mL at aconcentration of 40 mg/mL) to prostate cancer patients, degarelix iseliminated in a biphasic fashion, with a median terminal half-life ofapproximately 43 days.

The long half-life after subcutaneous administration is a consequence ofa very slow release of degarelix from the depot formed at the injectionsite(s).

The pharmacokinetic behavior of the drug is strongly influenced by itsconcentration in the injection suspension.

The resulting distribution volume in healthy elderly men isapproximately 1 L/kg. Plasma protein binding is estimated to beapproximately 90%.

Degarelix is subject to common peptidic degradation during the passageof the hepato-biliary system and is mainly excreted as peptide fragmentsin the feces. No significant metabolites were detected in plasma samplesafter subcutaneous administration. In vitro studies have shown thatdegarelix is not a substrate for the human CYP450 (cytochrome P450)system. Therefore, clinically significant pharmacokinetic interactionswith other drugs are unlikely to occur.

In healthy men, approximately 20% of a given dose of degarelix wasrenally excreted, suggesting that approximately 80% is excreted via thehepato-biliary system in humans. The clearance in healthy elderly men is35-50 mL/hr/kg.

Adverse Events (Side Effects)

Degarelix has been found to be generally well tolerated in clinicaltrials. The most commonly observed adverse reactions during therapy weredue to the expected physiological effects of testosterone suppression,mainly hot flushes and increased weight, and injection site relatedadverse events (injection site related side effects), mainly injectionsite pain and injection site erythema.

EXAMPLES Example 1 S-ALP Levels in Prostate Cancer Patients Treated withDegarelix Versus Leuprolide

Example 1 gives the results of the analyses of serum alkalinephosphatase (S-ALP) performed on patients undergoing treatment forprostrate cancer, using alternatively, degarelix (240/80 mg) andleuprolide (7.5 mg) treatments.

Methods:

Patients with histologically confirmed adenocarcinoma of the prostate(all stages), for whom androgen deprivation therapy was indicated wererecruited. Baseline characteristics were well balanced between groups.Approximately half of patients had locally advanced (29.2%) ormetastatic (20.5%) disease at baseline. A total of 610 patients (meanage 72 years, median testosterone was 39.3 ng/mL, and median PSA 19.0ng/mL) were randomized to 1 of 3 dosing regimens: degarelix s.c. 240 mgfor 1 month (initiation dose) followed by monthly maintenance doses of160 mg (n=202) or 80 mg (n=207), or monthly intramuscular injections ofleuprolide depot 7.5 mg (n=201). Patients receiving leuprolide couldalso receive bicalutamide for clinical flare protection.

S-ALP Analysis:

The S-ALP levels were measured in each patient at various time points,by taking a blood sample and analyzing for S-ALP. S-ALP levels weremeasured using a standardized colorimetric assay based on thep-nitrophenyl phosphate AMP buffer method. The normal range for S-ALP is44-147 IU/L. The S-ALP values in non-metastatic patients serve ascontrols. An ANOVA analysis with treatment and day as factors andbaseline value as covariate was used to determine between treatmentdifferences at Day 364. A repeated measures analysis (incorporating alltime points from Day 112) with treatment and day as factors and baselinevalue as covariate was used to assess between treatment differences fromDay 112 to Day 364.

Results:

The results of S-ALP analyses for the degarelix 240/80 mg and leuprolide7.5 mg groups in patients with advanced prostate cancer are presented inTable 2 and FIG. 1. In localized disease, S-ALP levels showed a smallbut gradual increase within normal range over the study period,irrespective of treatment group (leuprolide or degarelix). Similarly, inlocally advanced disease, a small increase was observed by the end ofthe study in both treatment groups. Table 2 shows that baseline S-ALPlevels are high in metastatic patients, and even more so in the patientswith Hb<130 g/L, whichever the treatment. However, after initial peaksin both groups, as described earlier for hormonal treatments, S-ALPlevels were suppressed below baseline with both degarelix 80 mg andleuprolide, though more significantly with degarelix. An initialincrease (peak) in S-ALP is associated with increased activity in bone,and metastatic patients experience a surge in S-ALP at the initiation ofall therapies having an effect on skeletal metastasis. This is a welldescribed phenomenon and totally independent of testosterone surge.

FIG. 1 compares the mean change from baseline of S-ALP levels versustime for the localized, locally advanced, and metastatic populations,using degarelix (240/80 mg) and leuprolide (7.5 mg) treatments. Theseresults clearly illustrate the long-term suppression of S-ALP usingdegarelix. A decrease in baseline S-ALP levels in a treated subjectsuffering from prostate cancer indicates a positive response to thetreatment-, for example by reducing skeletal metastatic activity.Conversely, an increase in S-ALP indicates increased metastaticactivity. FIG. 1 shows that degarelix treatment significantly reducesS-ALP (after an initial and expected surge) and then maintains thereduction for the duration of the study. Most significantly, S-ALP riseswith leuprolide later in the study, indicating a return of metastaticactivity. Such a return was not observed with degarelix untilsignificantly later (FIG. 3). Thus, FIG. 1 indicates that degarelix isable to reduce the level of skeletal metastases for a longer term (or atleast maintain the same level without increase). In contrast, leuprolidewas less effective in the short term, and much less effective in thelong term than degarelix. Similar results were obtained for the 240/160mg dose of degarelix.

This effect is further enhanced in patients with metastatic disease anda haemoglobin (Hb) content of Hb<130 g/L, when compared with metastaticdisease overall (see Table 2, and FIG. 2). Bone metastases affect bonemarrow and a patient with bone metastasis may become anaemic. A lowerthan normal Hb in patients with bone metastasis is indicative of greaterdegree of metastasis (in other words, is indicative of more seriousdisease). Table 2 and FIG. 2 demonstrate that the long term suppressionof S-ALP by degarelix was even more effective in this sub-populationhaving more serious disease.

In patient groups with baseline PSA≦50 ng/mL, a general trend towardssmall increases in S-ALP levels was observed in both treatment groupsover time. However, a different trend is seen in patients with baselinePSA≧50 ng/mL. Table 2 (2nd section) compares the S-ALP values (IU/L) forthe Baseline PSA (<10 ng/mL), (10-20 ng/mL), (20-50 ng/mL), (>50 ng/mL)populations, using degarelix (240/80 mg) and leuprolide (7.5 mg)treatments. The same pattern of S-ALP response as described in FIG. 1was seen in patients with baseline PSA≧50 ng/mL (see FIG. 4 and Table 2,2nd section). Initial reductions were not maintained with leuprolide,with levels finishing above baseline by the study end (e.g., at 364days) reflecting bone lesions in these patients. These initial decreasesin ALP levels were, by contrast, maintained throughout the study usingdegarelix (240/80 mg treatment regimen). These results indicate thatdegarelix may be particularly effective in treating subjects (patients)having prostate cancer with baseline PSA≧50 ng/mL.

TABLE 2 S-ALP values (IU/L) for the Localized, Locally advanced,Metastatic populations, and Metastatic (Hb < 130 g/L) subpopulations,using Degarelix (240/80 mg) and Leuprolide (7.5 mg) treatments. S-ALPvalues (IU/L) Degarelix Leuprolide 240/80 mg (n = 207) 7.5 mg (n = 201)Mean change from Mean change from baseline baseline Mean Day Day DayMean Day Day Day N Baseline 112 224 364 N Baseline 112 224 364 Diseasestage (a) Localized 68 56 +5 +8 +10 62 56 +5 +7 +9 Locally 64 57 +6 +7+10 52 62 −1 −1 +6 advanced Metastatic 37 200 −90 −100 −90 47 150 −20−50 0 Metastatic 27 300 −160 −200 −230 28 190 −30 −70 −10 (Hb < 130 g/L)Mean Baseline PSA (b) <10 54 56 +4.5 +5.5 +7 63 56 +4.5 +6 +7.5 ng/mL10-20 52 55 +5 +8 +13 44 55 +5 +8 +8 ng/mL 20-50 52 64 +5 +7.5 +4.5 3864 +5 +8.5 +11 ng/mL >50 48 170 −60 −70 −60 55 150 −40 −60 +10 ng/mL

Section (a) of Table 2 shows the S-ALP values (IU/L) for the localized,locally advanced, metastatic populations and metastatic (Hb<130 g/L)subpopulation, using degarelix (240/80 mg) and leuprolide (7.5 mg)treatments.

Section (b) of Table 2 shows the S-ALP values (IU/L) for the baselinePSA (<10 ng/mL), (10-20 ng/mL), (20-50 ng/mL), (>50 ng/mL) populations,using degarelix (240/80 mg) and leuprolide (7.5 mg) treatments.

Conclusions:

Patients with metastatic disease and/or those with PSA levels≧50 ng/mLat baseline experienced greater reductions in S-ALP levels withdegarelix than leuprolide. More significantly, the rise (or return tobaseline level) in S-ALP with leuprolide late in the study, indicatingreturn of metastatic activity, was not observed with degarelix (240/80mg) until much later. Conversant with this finding was the observationthat patients in the degarelix group did not display signs of therapyfailure late in the year's treatment, as indicated by significantlylower ALP levels at day 364. Finally, this effect is further enhanced inpatients with metastatic disease and exhibiting a haemoglobin content ofHb<130 g/L, when compared with metastatic disease overall. These resultsthus indicate that degarelix may be able to reduce and/or maintain thelevel of skeletal metastases better than leuprolide.

Example 2 PSA Failure in Prostate Cancer Patients Treated with DegarelixVersus Leuprolide

This example provides additional PSA level analyses from the phase IIIclinical trial CS21 (described herein), which examined the efficacy andsafety of degarelix compared with leuprolide over 12 months of prostatecancer treatment. In particular, analysis of a secondary endpoint termedPSA failure revealed a surprisingly advantageous effect of degarelixtreatment as compared to leuprolide treatment, particularly for patientswith metastatic stage prostate cancer.

Prostate-specific antigen (PSA) is a commonly used marker in thediagnosis of prostate cancer and has more recently also been used tomonitor response to treatment as well as disease recurrence andprogression (Fleming et al. (2006) Nat. Clin. Pract. Oncol. 3: 658-67;Lilja, et al. (2008) Nat. Rev. Cancer 8: 268-78). In general, higherlevels of PSA are associated with more severe forms of prostate cancer,with metastatic stage prostate cancer being associated with the highestlevels of PSA (e.g., >50 ng/mL). Accordingly, rising PSA levels inpatients undergoing prostate cancer treatment are associated withincomplete or failed efficacy of the treatment.

For this analysis, PSA failure (a secondary endpoint) was defined as twoconsecutive increases in PSA of 50% and ≧5 ng/mL compared with nadir.The time to PSA failure was defined as the number of days from firstdosing to where an increase in serum PSA of ≧50% from nadir and ≧5ng/mL, measured on two consecutive occasions at least two weeks apart,was noted. The second occasion was the time point of meeting thecriterion. PSA failure rates were also analyzed by disease stage andbaseline PSA level. In these analyses, the focus was on a comparison ofdegarelix 240/80 mg versus leuprolide 7.5 mg as this is the degarelixdose now approved by the FDA for the treatment of advanced prostatecancer.

The incidence of PSA failure was lower in the degarelix 240/80 mg groupcompared with the other two treatment groups. The probability ofcompleting the study without experiencing PSA failure by day 364 washighest for the degarelix 240/80 mg group (91.1%; 95% Cl: 85.9-94.5).The observed day 364 probability for leuprolide 7.5 mg was 85.9% (95%Cl: 79.9-90.2).

PSA Failure—By Baseline Disease Stage

PSA failure occurred more frequently in patients with advanced disease,across all treatment groups; the majority of PSA failures occurred inpatients with metastatic disease at baseline (FIG. 5). In this subgroupof patients, a smaller proportion of PSA failures were observed duringdegarelix 240/80 mg treatment compared with leuprolide (21.6% vs 36.2%;p=0.1559). Accordingly, the degarelix treatment protocol provides aneffective treatment for metastatic stage prostate cancer as measured bya reduced incidence of PSA failure.

PSA Failure—By Baseline PSA Level

PSA failure occurred more frequently in patients with higher baselinePSA level, across all treatment groups; the majority of PSA failuresoccurred in patients with baseline PSA>50 ng/mL (FIG. 6). In thissubgroup of patients, a smaller proportion of PSA failures were observedduring degarelix 240/80 mg treatment compared with leuprolide (29.2% vs40.0%; p=0.10). Similarly, fewer patients with baseline PSA 20-50 ng/mLhad PSA failure during degarelix treatment. Accordingly, the degarelixtreatment protocol provides an effective treatment as measured by areduced incidence of PSA failure in subjects with advanced stageprostate cancer, as reflected in baseline PSA levels of >50 ng/mL.

Example 3 Clinical Study of Degarelix for the Treatment of ProstateCancer

In this example, an open-label, multi-center, randomized, parallel-groupstudy was conducted to investigate the efficacy and safety of degarelixone month dosing regimens using either of two different once-a-monthdosing regimens, 160 mg (40 mg/mL) or 80 mg (20 mg/mL). These degarelixdosing regimens were compared to leuprolide at 7.5 mg in patients withprostate cancer requiring androgen ablation therapy.

The study also investigated whether degarelix is safe and effective withrespect to achieving and maintaining testosterone suppression tocastrate levels, evaluated as the proportion of patients withtestosterone suppression≦0.5 ng/mL during 12 months of treatment. Thestudy assessed serum levels of testosterone and prostate-specificantigen (PSA) during the first 28 days of treatment using a degarelixdosing regimen as compared to leuprolide 7.5 mg. The study furthercompared the safety and tolerability using a degarelix dosing regimencompared to treatment with leuprolide 7.5 mg, and, further, comparedtestosterone, luteinizing hormone (LH), follicle-stimulating hormone(FSH), and PSA response with a degarelix dosing regimen compared toleuprolide 7.5 mg. The study further compared patient reported outcomes(quality of life factors and hot flushes) using a degarelix dosingregimen as compared to leuprolide 7.5 mg during treatment. The studyalso evaluated the pharmacokinetics of the degarelix dosing regimensinvestigated. Finally, the study examined the effects of using thedegarelix treatment on patients suffering from different stages ofcancer.

Study Design

A total of 620 patients were randomized 1:1:1 to one of three treatmentgroups. Of these, 610 patients (mean age 72 years, median PSA 19.0ng/mL) were administered degarelix. Ten randomized patients withdrewfrom the study before dosing.

Patients in two treatment groups received a degarelix starting dose of240 mg at a concentration of 40 mg/mL (240@40) on day 0 administered astwo equivalent subcutaneous (s.c.) injections of 120 mg each.Thereafter, patients received 12 additional single s.c. degarelix dosesof either 80 mg at a concentration of 20 mg/mL (80@20: degarelix 240/80mg group) or 160 mg at a concentration of 40 mg/mL (160@40: degarelix240/160 mg group) administered s.c. every 28 days. In the thirdtreatment group, patients received active treatment with leuprolide 7.5mg on day 0 and every 28 days administered as a single intramuscular(i.m.) injection. For patients receiving treatment with leuprolide 7.5mg, bicalutamide could be given as clinical flare protection at theinvestigator's discretion.

Patients were stratified according to geographic region (Central andEastern Europe, Western Europe and The Americas) and body weight (<90 kgand ≧90 kg).

Degarelix 240/160 mg Group

This group received an initial dose of 240 mg at a concentration of 40mg/mL (240@40) on day 0. This starting dose was administered as twoequivalent subcutaneous (s.c.) injections of 120 mg each. The group thenreceived 12 maintenance doses of 160 mg at a concentration of 40 mg/mL(160@40) as single s.c doses of degarelix every 28 days.

Degarelix 240/80 mg Group

This group also received an initial dose of 240 mg at a concentration of40 mg/mL (240@40) on day 0. This starting dose was administered as twoequivalent s.c. injections of 120 mg each. The group then received 12maintenance doses of 80 mg at a concentration of 20 mg/mL (80@20) assingle s.c doses of degarelix every 28 days.

Leuprolide 7.5 mg Group

This group received the reference therapy leuprolide 7.5 mg. Thistreatment was administered as a single intramuscular (i.m.) injection,once every 28 days starting at day 0. These treatment regimens aresummarized in Table 3 below.

TABLE 3 Treatment Methodology Treatment Group Starting Dose MaintenanceDoses Degarelix 240@40 (as 2 160@40 (as 12 single 240/160 mg doses onday 0) doses, one every 28 days) Degarelix 240@40 (as 2 80@20 (as 12single 240/80 mg doses on day 0) doses, one every 28 days) Leuprolide7.5 mg administered at day 0 and every 28 days 7.5 mg via singleintramuscular injection. Bicalutamide was given at the Investigator'sdiscretion.

Patients were monitored on an ongoing basis and visited the clinic atmonthly intervals up to one year. Patients were observed clinically forat least 1 hour after each administration of study drug. Patients whocompleted the study and met appropriate criteria were offered theopportunity to receive long-term treatment and support in an extensionstudy.

A total of 807 patients were screened and 620 patients were randomized1:1:1 into three treatment groups, degarelix 240/160 mg, degarelix240/80 mg and leuprolide 7.5 mg. Of the 620 patients randomized, 610patients actually received study medication including 202, 207 and 201patients in the degarelix 240/160 mg, degarelix 240/80 mg and leuprolide7.5 mg treatment groups, respectively. A total of 504 patients completedthe study.

Diagnosis and Criteria for Study Inclusion

Males aged 18 years and over with histologically confirmed (Gleasongraded) adenocarcinoma of the prostate (all stages), in whom androgenablation treatment was indicated (except for neoadjuvant hormonaltherapy) were eligible to participate. Signed informed consent wasobtained before any study-related activity occurred. Patients were tohave a baseline testosterone level>1.5 ng/mL and a PSA level of ≧2 ng/mLat the time of screening. Patients with rising PSA after havingundergone prostatectomy or radiotherapy with curative intent could beincluded in the study. Patients were required to have an ECOG score of≦2 and a life expectancy of at least 12 months. Previous or presenthormonal management of prostate cancer (surgical castration or otherhormonal manipulation, e.g. GnRH agonists, GnRH antagonists,antiandrogens, or estrogens) resulted in exclusion from the study.However, in patients having undergone prostatectomy or radiotherapy withcurative intention, neoadjuvant hormonal treatment was accepted for amaximum duration of 6 months provided that this treatment had beenterminated for at least 6 months prior to the screening visit.Concurrent treatment with a 5-α-reductase inhibitor also resulted inexclusion from the study. Patients who were candidates for a curativetherapy (i.e. radical prostatectomy or radiotherapy) were excluded.Patients with histories of severe hypersensitivity reactions orclinically significant disorders (other than prostate cancer) that mightaffect the conclusion of the study as judged by the investigator werenot eligible to enter into the study. Patients with a marked baselineprolongation of QT/QTcF interval (>450 msec) or that had usedconcomitant medications that may prolong QT/QTcF interval or who had ahistory of additional risk factors for Torsade de Pointes ventriculararrhythmias were excluded. Patients who had elevated serum ALT or totalbilirubin levels above upper level of normal range at the screeningvisit or who had known or suspected hepatic, symptomatic biliary diseasewere also excluded. Patients were also excluded if they had a knownhypersensitivity to any component of the investigational products. Inaddition, patients with any form of cancer within the last five years,with the exception of prostate cancer and surgically removed basal orsquamous cell carcinoma of the skin, were excluded from the study.Patients who had a mental incapacity or language barriers precludingadequate understanding or co-operation were also ineligible toparticipate in the study. No other investigational drug was to beadministered within 28 days preceding the screening visit.

Duration of Treatment

Patients in the degarelix treatment groups received a starting dose of240@40 on day 0 and 12 maintenance doses of 160@40 (degarelix 240/160 mggroup) or 80@20 (degarelix 240/80 mg group) every 28 days.Administration of degarelix took place on day 0, day 28 (±2 days) andevery 28 day (±7 days) thereafter until the end of study visit, i.e.,day 364 (±7 days). Patients who completed the study and met appropriatecriteria were offered the opportunity to receive long-term treatment andsupport in an extension study.

Patients in the reference therapy group received treatment withleuprolide 7.5 mg on day 0 and every 28 days thereafter for 12maintenance doses. Patients who completed the study received thirteendoses in total. Patients who completed the study and met appropriatecriteria were offered a switch to degarelix treatment in a continuingstudy. These patients were randomized to degarelix treatment 240/80 mgor 240/160 mg. On day 0 of the study, patients previously treated withleuprolide 7.5 mg in study CS21 received a 240 mg (40 mg/mL) degarelixstarting dose followed by monthly maintenance doses of either 80 mg (20mg/mL) or 160 mg (40 mg/mL).

Patients in the comparator group were treated with leuprolide 7.5 mgpre-filled, dual-chamber syringe for intramuscular (i.m.) injection.Patients received leuprolide 7.5 mg on day 0 and every 28 dayssubsequently, administered as a single i.m. injection. At theinvestigator's discretion, bicalutamide could be given as clinical flareprotection.

Criteria for Evaluation of Efficacy

In an aspect of the invention, the composition (or medicament) may befor treatment wherein the subject has at least a 95% likelihood ofmaintaining a therapeutically low serum testosterone level of less thanor equal to 0.5 ng/mL by day 28 of treatment, for example wherein thesubject has at least a 95% likelihood of maintaining a therapeuticallylow serum testosterone level of less than or equal to 0.5 ng/mL from day28 to day 364 of treatment.

The composition (or medicament) may be for treatment wherein the subjecthas at least a 60% decrease (for example at least a 75% decrease) inprostate specific antigen (PSA) by day 28 of treatment. The composition(or medicament) may be for treatment with at least an 80% likelihood ofmaintaining a prostate specific antigen (PSA) level of less than 5 mg/mLduring treatment.

The primary efficacy endpoint was the probability of testosterone levelsremaining ≦0.5 ng/mL from day 28 through day 364.

The secondary efficacy endpoints were: the proportion of patients withtestosterone surge during the first 2 weeks of treatment; the proportionof patients with testosterone level≦0.5 ng/mL at day 3; the percentagechange in PSA from baseline to day 28; the probability oftestosterone≦0.5 ng/mL from day 56 through day 364; the levels of serumtestosterone, LH, FSH and PSA over time through the study; the time toPSA failure, defined as two consecutive increases of 50%, and at least 5ng/mL as compared to nadir; degarelix concentration over the first monthand trough levels at day 308 and 336; the frequency and size oftestosterone increases at day 255 and/or 259 compared to thetestosterone level at day 252; the quality of life on days 0, 28, 84,168 and end of study visit; the frequency and intensity of hot flushesexperienced (scored daily from study start until end of study visit). Inaddition, two further secondary endpoints were added: the probability ofsufficient testosterone response from day 28 through day 364 (a patientwas considered to have insufficient testosterone response if he had onetestosterone value>1.0 ng/mL or two consecutive testosterone values>0.5ng/mL at day 28 onwards); and the percentage change in PSA from baselineto day 14.

Criteria for Evaluation of Safety

The safety variables for this study were assessed on the following: thefrequency and severity of adverse events (AEs); the presence ofclinically significant changes in laboratory parameters (clinicalchemistry, hematology and urinalysis); changes in electrocardiograms(ECGS) and vital signs; changes detected by physical examination; andbody weight.

Body weight was measured at screening and the end of study visit. Height(without shoes) was measured at screening. Body mass index (BMI) isdefined as the individual's body weight divided by the square of theirheight. The formulas universally used in medicine produce a unit ofmeasure of kg/m². Body mass index may be accurately calculated using anyof the formulas known in the art.

Statistical Methods

All statistical analyses were performed, and summary statisticscalculated, using statistical analysis software SAS™ version 9 orhigher. The populations for analysis were:

The intention-to-treat (ITT) analysis set included all randomizedpatients who received at least one dose of degarelix.

The per protocol (PP analysis set) comprised all the ITT analysis setwithout any major protocol violations.

The safety population was identical to the ITT analysis set, andtherefore all safety analyses were performed on the ITT analysis set.

The primary efficacy endpoint was analyzed for both the ITT and PPanalysis sets, with the ITT analysis set considered primary. The primaryefficacy endpoint was analyzed using the Kaplan Meier method. For eachof the three treatment groups, testosterone response rates with 95%confidence interval (CI) were calculated by log-log transformation ofsurvivor function. Differences between the degarelix treatment groupsand leuprolide 7.5 mg were assessed using a 97.5% CI calculated bynormal approximation using pooled standard error.

To assess the efficacy of degarelix, two hypotheses were tested:

(1) The Food & Drug Administration (FDA) criterion was to determinewhether the lower bound of the 95% confidence interval (CI) for thecumulative probability of testosterone≦0.5 ng/mL from day 28 to day 364was no lower than 90%.

(2) The European Medicines Agency (EMEA) criterion was to determinewhether degarelix was non-inferior to leuprolide 7.5 mg with respect tothe cumulative probability of testosterone≦0.5 ng/mL from day 28 to day364. The non-inferiority limit for the difference between treatments(degarelix versus leuprolide 7.5 mg) was −10 percentage points.

All secondary efficacy endpoints were analyzed for both the ITT and PPanalysis sets, unless otherwise stated. The proportion of patients withtestosterone surge during the first 2 weeks of treatment was analyzedusing Fisher's exact test. Fisher's exact test was also used to analyzethe proportion of patients with testosterone level≦0.5 ng/mL at day 3.The percentage change in PSA from baseline to day 28 endpoint wasanalyzed by a Wilcoxon test. For both Fisher's exact test and theWilcoxon test, separate data presentations were made by treatment group,geographic region, weight strata (<90 kg, ≧90 kg) and for the leuprolide7.5 mg subgroup.

The secondary endpoints, probability of testosterone≦0.5 ng/mL from day56 through day 364, time to PSA failure, and probability of sufficienttestosterone response from day 28 through day 364 were analyzed by theKaplan-Meier method.

Efficacy Results

The primary objective of this study was to demonstrate the effectivenessof degarelix in achieving and maintaining testosterone suppression tocastrate levels, evaluated as the proportion of patients withtestosterone suppression≦0.5 ng/mL during 12 months of treatment.

The results show that degarelix delivered at the 240/80 mg dosingregimen produced a rapid and effective suppression in testosteronelevels, which remained low throughout the 364 day period of treatment(FIG. 7).

Kaplan-Meier estimates of the probabilities of testosterone≦0.5 ng/mLfrom day 28 to day 364 were 98.3%, 97.2% and 96.4% for the degarelix240/160 mg, degarelix 240/80 mg and leuprolide 7.5 mg groups,respectively. For all three treatment groups, the lower bound of the 95%CI was above the pre-specified 90% threshold. Treatment with degarelixwas demonstrated to be non-inferior to leuprolide 7.5 mg therapy withrespect to the probability of testosterone≦0.5 ng/mL from day 28 to day364. For both degarelix treatment groups, the entire 97.5% CI for thedifference in probability compared with the leuprolide 7.5 mg group wasgreater than the non-inferiority limit of −10 percentage points. Thus,the study fulfilled the FDA and EMEA criteria for efficacy.

The robustness of the results for the primary efficacy endpoint wassupported by an observed cases analysis, which produced similarestimates of the overall proportion of patients with testosterone<0.5ng/mL from day 28 to day 364 for the degarelix 240/160 mg, degarelix240/80 mg and leuprolide 7.5 mg groups of 98.2%, 97.0% and 96.0%,respectively. The findings of the primary analysis were furthersupported by a secondary efficacy analysis of the probability oftestosterone≦0.5 ng/mL from day 56 to day 364.

As expected, a significantly higher proportion of patients in theleuprolide 7.5 mg group (80.1%) had a testosterone surge (increase ≧15%from baseline) during the first two weeks of treatment compared with thepooled degarelix groups (0.2%: one patient) (p<0.0001, Fisher's exacttest). The patient treated with degarelix can be considered to be anartifact as this patient had low testosterone at baseline (0.0065 ng/mL)thus a surge from such a low baseline value was not remarkable.Conversely, 96% of patients receiving degarelix exhibited testosteronesuppression on day 3 compared with no patients in the leuprolide 7.5 mggroup (p<0.0001, Fisher's exact test). As shown in FIGS. 7 and 8, thedegarelix 240/80 mg dosing regimen rapidly and efficiently suppressedtestosterone levels, while leuprolide 7.5 mg acted much more graduallyand only after an initial testosterone surge.

As shown in FIG. 9, the degarelix 240/80 mg dosing regimen also produceda more rapid and efficient reduction in PSA levels than did treatmentwith leuprolide 7.5 mg. A rapid reduction in PSA levels was observed forpatients treated with degarelix. In contrast, PSA levels in theleuprolide 7.5 mg group reached a plateau during the first week oftreatment before decreasing exponentially to suppressed levels. Therewas a significantly greater reduction in median PSA levels from baselinethat was observed on day 14 and day 28 for degarelix patients comparedwith leuprolide 7.5 mg patients (p<0.0001, Wilcoxon test). Theprobability of a PSA observation from the pooled degarelix groups beingless than one from the leuprolide 7.5 mg group was slightly higher onday 14 (0.82) than on day 28 (0.70). The probability of completing thestudy without experiencing PSA failure was highest in the degarelix240/80 group (91.2%) and slightly lower (˜85.8%) for both the degarelix240/160 mg and leuprolide 7.5 mg groups, although this difference wasnot statistically significant.

Anti-androgen therapy, as per protocol, was given to 22 patients in theleuprolide 7.5 mg group at the start of treatment for flare protection.PSA data for these patients showed a greater median percentage changefrom baseline at day 14 (61.7% reduction) and day 28 (89.1%) compared tothose patients in the leuprolide 7.5 mg group who did not receiveanti-androgen therapy, where the percentage reduction was 15.3% and61.7% at days 14 and 28, respectively. It should be noted that themedian percentage change in PSA levels in the leuprolide plusantiandrogen patients was similar to those patients treated withdegarelix, thereby confirming that degarelix is more effective thanconventional GnRH agonist therapy at suppressing PSA at the start oftreatment. Degarelix does not require additional concomitant medicationas prophylaxis for flare, yet a starting dose of 240 mg has a similareffect on PSA levels as the combination of GnRH agonist plusanti-androgen.

The profiles for serum levels of LH over time were similar to thoseobserved for testosterone. Following administration of degarelix, medianLH levels for the ITT analysis set decreased rapidly and were <0.7 IU/Lon day 1, a decrease of approximately 88% from baseline. For bothdegarelix treatment groups median LH levels remained suppressed untilthe end of the study on day 364. In contrast, a surge in median LHlevels was observed for patients in the leuprolide 7.5 mg group, whichpeaked at 31.0 IU/L on day 1 (>400% increase from baseline) beforedecreasing exponentially to 0.035 IU/L by day 56 and remaining at thislevel until day 364 (see FIG. 10).

A rapid decrease in FSH levels was also observed in patients treatedwith degarelix. Administration of degarelix resulted in a reduction inmedian FSH levels to ≦1.5 IU/L by day 7, a >80% decrease from baseline.For both degarelix treatment groups median FSH levels remainedsuppressed until the end of the study on day 364. For patients in theleuprolide 7.5 mg group there was an initial surge in FSH levels similarto that observed for LH levels which peaked at 22.5 IU/L on day 1 (146%increase from baseline) before decreasing exponentially to 2.0 IU/L byday 14. Median FSH subsequently increased around day 56 to a plateau ofapproximately 4.40 IU/L and stayed there until day 364 (see FIG. 11).

The pharmacodynamic profile for degarelix was characteristic of a GnRHantagonist with serum levels of testosterone, LH and FSH suppressedrapidly. In contrast, for patients in the leuprolide 7.5 mg group, serumlevels of testosterone, LH and FSH increased rapidly within the firstweek of treatment before falling to suppress levels. (See FIGS. 7, 8, 10and 11).

Safety Results

Safety and tolerability were evaluated by observed and reportedtreatment-emergent AEs, including injection site reactions,haematological, clinical chemistry and urinalysis laboratory parameters,vital signs/clinical observations, and body weight measurements andphysical examination, ECGs and concomitant medication.

Safety parameters were evaluated for all patients included in the ITTanalysis set, comprising all 610 randomized patients who received atleast one dose of study medication.

The invention claimed is:
 1. A method of treating metastatic stageprostate cancer in a subject, the method comprising: identifying asubject with metastatic stage prostate cancer comprising measuring thesubject's baseline serum alkaline phosphatase (S-ALP) level; andreducing the subject's S-ALP level with respect to the baseline level byadministering an initial dose of degarelix ranging from about 160 toabout 320 mg to the subject; and administering at least one maintenancedose of degarelix ranging from about 60 mg to about 160 mg to thesubject, wherein the at least one maintenance dose is administeredapproximately 20 days to 36 days, after the previous dose of degarelixfor a duration of treatment ranging from 20 days to 450 days; andfurther, wherein the S-ALP level is reduced for the duration oftreatment relative to the initial S-ALP level measured at the start oftreatment.
 2. The method of claim 1, wherein the initial dose ofdegarelix is about 240 mg, and the at least one maintenance dose ofdegarelix is about 80 mg administered to the subject approximately 28days after the previous dose of degarelix.
 3. The method of claim 1wherein identifying the subject comprises measuring the baseline S-ALPlevel in the subject of 150 IU/L or greater.
 4. The method of claim 1,wherein identifying the subject comprises measuring the baseline S-ALPlevel in the subject of 160 IU/L or greater.
 5. The method of claim 1,wherein identifying the subject comprises measuring the baseline S-ALPlevel in the subject of 200 IU/L or greater.
 6. The method of claim 1,wherein identifying the subject comprises measuring the baseline S-ALPlevel in the subject of 300 IU/L or greater.
 7. The method of claim 1,wherein the treated subject's S-ALP level is reduced by at least 60 IU/Lfrom the baseline level between day 112 and day 364 of treatment.
 8. Themethod of claim 1, wherein the treated subject's S-ALP level is reducedby at least 50 IU/L from the baseline level between day 60 and day 364of treatment.
 9. The method of claim 1, wherein the treated subject'sS-ALP level is reduced by at least 50 IU/L from the baseline levelbetween day 364 and day 450 of treatment.
 10. The method of claim 1,wherein the treated subject's S-ALP level is reduced by at least 90 IU/Lfrom the baseline level between day 112 and day 364 of treatment. 11.The method of claim 1, wherein the treated subject's S-ALP level isreduced by at least 160 IU/L from the baseline level between day 112 andday 364 of treatment.
 12. The method of claim 1, wherein the treatedsubject has at least a 95% likelihood of having a therapeutically lowserum testosterone level of less than or equal to 0.5 ng/mL by day 28 oftreatment.
 13. The method of claim 1, wherein the treated subject has atleast a 95% likelihood of maintaining a therapeutically low serumtestosterone level of less than or equal to 0.5 ng/mL from day 28 to day365 of treatment.
 14. The method of claim 1, comprising administeringfrom 1 to 21 maintenance doses of degarelix to the subject, wherein eachmaintenance dose is administered approximately 20 days to 36 days afterthe previous dose of degarelix.
 15. A method of treating metastaticstage prostate cancer in a subject. the method comprising: identifying asubject with metastatic stage prostate cancer comprising measuring thesubject's baseline serum alkaline phosphatase (S-ALP) level andmeasuring the subject's baseline prostate-specific antigen (PSA) level;and reducing the subject's S-ALP level with respect to the baselinelevel by administering an initial dose of degarelix ranging from about160 mg to about 320 mg to the subject; and administering at least onemaintenance dose of degarelix ranging from about 60 mg to about 160 mgto the subject approximately 20 days to 36 days after the previous doseof degarelix for a duration of treatment.
 16. The method of claim 15,wherein identifying the subject comprises measuring the baseline S-ALPlevel in the subject of 150 IUIL or greater.
 17. The method of claim 15,wherein identifying the subject comprises measuring the baseline S-ALPlevel in the subject of 160 IUIL or greater.
 18. The method of claim 15,wherein the treated subject's S-ALP level is reduced by at least 60 IUILfrom the baseline level between day 112 and day 364 of treatment.